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Cuello Garibo, J.A. 2017

Caging ruthenium complexes with non-toxic ligands for photoactivated chemotherapy

Doctoral Thesis

open access

The main goal of the research described in this thesis was the development of new photoactivated chemotherapy (PACT) ruthenium(II) complexes bearing a non-toxic photolabile ligand. We first... Show moreThe main goal of the research described in this thesis was the development of new photoactivated chemotherapy (PACT) ruthenium(II) complexes bearing a non-toxic photolabile ligand. We first investigated whether non-toxic ligands such as L-proline, 2-(methylthio)methylpyridine (mtmp), or 3-(methylthio)propylamine (mtpa), once coordinated to ruthenium(II) complexes, could be photosubstituted upon visible light irradiation. The lipophilicity, and in some cases the strain of the ruthenium(II) complexes, were systematically varied and the effects of such variations on the cytotoxicity of the complexes in the dark and under light irradiation were studied. In the second part, the best ligand candidates (i.e. mtmp and mtpa) were coordinated to cyclometalated ruthenium complexes of the type [Ru(bpy)(phpy)(S,N)]PF6 (bpy = 2,2’-bipyridine and phpy = 2-phenylpyridine), to shift the absorption of the complex to the red region of the spectrum. The photosubstitution properties of these cyclometallated complexes were investigated in detail. The most promising ruthenium complexes were tested in cancer cell monolayers under hypoxic conditions (1% O2) to investigate their mode of action and distinguish between PACT and PDT. Show less

Lameijer, L.N. 2017

The synthesis and biological applications of photo-activated ruthenium anticancer drugs

Doctoral Thesis

open access

Conventional chemotherapy often suffers from a lack of specificity, affecting both normal and cancer cells. Light-activated drugs provide spatial and temporal control over their activity, providing... Show moreConventional chemotherapy often suffers from a lack of specificity, affecting both normal and cancer cells. Light-activated drugs provide spatial and temporal control over their activity, providing a possible solution for this problem. This dissertation describes the synthesis and biological applications of (blue/green/red) light-activated ruthenium polypyridyl drugs as potential prodrugs against cancer. Show less

Liu, B. 2017

Iminosugars as glucosylceramide processing enzymes inhibitors: design, synthesis and evaluation

Doctoral Thesis

open access

This Thesis describes the design, synthesis and evaluation as glycoprocessing enzyme inhibitors of focused libraries of iminosugars. In the studies described, 1-deoxynojirimycin (DNJ), and its... Show moreThis Thesis describes the design, synthesis and evaluation as glycoprocessing enzyme inhibitors of focused libraries of iminosugars. In the studies described, 1-deoxynojirimycin (DNJ), and its known N-alkylated derivatives, served as starting points. DNJ modifications presented here include alteration of the substitution pattern of the piperidine core structure; variation in the N substituent, or a combination of the two. Biological evaluation of the synthesized compounds focused on the glycoprocessing enzymes involved in glucosylceramide metabolism: glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA1) and neutral glucosylceramidase (GBA2), and in all examples presented the inhibitory potency of newly synthesized compounds are compared with that of literature compounds. Show less

Ganapathy, S. 2017

Improvisations in phototrophy. Protein engineering and functional investigation of rhodopsin proton-pumps

Doctoral Thesis

open access

Microbial rhodopsins are photosensitive pigments implemented in the growth and adaptation of a large population of microorganisms. These relatively simple, tunable photosystems use a molecule... Show moreMicrobial rhodopsins are photosensitive pigments implemented in the growth and adaptation of a large population of microorganisms. These relatively simple, tunable photosystems use a molecule of retinal as a chromophore to facilitate the conversion of sunlight to chemical energy. Retinal-based phototrophy is believed to sustain the phototrophic balance of various biospheres and has several important biotechnological applications. In this thesis, we propose the use of microbial rhodopsins as an alternative photosystem in a complementary approach towards more efficient use of photons in the solar spectrum. Towards this end, we describe the adaptation of two rhodopsin proton-pumps, namely proteorhodopsin and Gloeobacter rhodopsin, to shift their action spectrum into the near-infrared region. Several red-shifted variants of were generated by utilizing a combination of retinal analogs with specific opsin mutations. We also constructed a novel directed-evolution set-up, which allows us to generate a library of red-shifted mutants with simultaneous screening for spectral shifts and proton-pumping ability. Finally, the impact of a detergent or lipid microenvironment was tested on the various pigments generated in this study. Our results have important prospects in a number of biotechnological fields such as optogenetics, membrane-sensor technology and as a complementary photosystem for oxygenic photosynthesis. Show less

Noteborn, W.E.M. 2017

Supramolecular polymer materials for biomedical applications and diagnostics

Doctoral Thesis

open access

Self-assembly is an abundant process in nature and is vital to many processes in living organisms. During the last decade the fields of supramolecular chemistry and polymer science have made... Show moreSelf-assembly is an abundant process in nature and is vital to many processes in living organisms. During the last decade the fields of supramolecular chemistry and polymer science have made an integrated effort in the design, synthesis and application of supramolecular polymers. Supramolecular polymers rely on relatively weak non-covalent interactions such as hydrogen bonding, solvophobicity and π-stacking to self-assemble using a wide array of natural and artificially designed interaction motifs. Using these principles, both end-functionalized polymers interacting via molecular recognition and stacked monomers self-assembling into one-dimensional structures have been demonstrated. A uniquely naturally-occurring supramolecular polymer is DNA which, apart from its role in genetics, can be used as a building block for both structural and dynamic applications such as making well-organized three-dimensional lattices or reconfigurable and autonomously operating DNA-based devices. As every class of materials has their own advantages, designing multicomponent materials from multiple types of building blocks such as DNA, and supramolecular and covalent polymers, has the potential to create highly advanced, organized and responsive materials both from structural and functional points of view. This dissertation has focused on designing such multicomponent functional supramolecular materials for biomedical applications and diagnostics. Show less

Wijdeven, R.H.M. 2017

Novel regulators of endosome dynamics, MHCII antigen presentation and chemosensitivity

Doctoral Thesis

open access

The aim of my work was to identify novel proteins that are involved in different aspects of disease biology, in the hope that we can target these to treat the disease. Using large-scale screening... Show moreThe aim of my work was to identify novel proteins that are involved in different aspects of disease biology, in the hope that we can target these to treat the disease. Using large-scale screening technologies, I found a novel regulator of chemosensitivity to the anti-cancer drugs etoposide and doxorubicin. Furthermore, novel proteins and drugs that target MHCII antigen presentation were picked up. Interestingly, one of these drugs is currently used in the clinic to treat MHCII-dependent autoimmune diseases, but for which the mechanism of action is unknown. Lastly, these screens yielded enzymes that control the dynamics of endosomes in the cell, which can potentially be targeted in cancers that rely on overactivation of growth signaling receptors. Taken together, my work has provided new potential targets for the treatment or classification of several tumor types, as well as a potential mechanism of action for a widely used drug. Show less

Pawlak, J.B. 2017

Bioorthogonal Antigens

Doctoral Thesis

open access

The aim of this thesis is to explore the use of Bioorthogonal Antigens to study the cross-presentation pathway. Bioorthogonal Antigens are antigens carrying bioorthogonal groups in specific... Show moreThe aim of this thesis is to explore the use of Bioorthogonal Antigens to study the cross-presentation pathway. Bioorthogonal Antigens are antigens carrying bioorthogonal groups in specific amino acid positions within the epitope region that can be reacted selectively within/on the cell using bioorthogonal ligation strategies. Incorporation of bioorthogonal groups into antigens has an advantage over other methods because most of the groups are stable to proteolysis and are small enough to have a minimal impact on routing and loading onto MHC-I molecules. In the future, these antigens have potential to be applied for imaging of the entire cross-presentation pathway using a single bioorthogonal handle. Show less

Beenakker, T.J.M. 2017

Design and development of conformational inhibitors and activity-based probes for retaining glycosidases

Doctoral Thesis

open access

Glycosidases are essential in fundamental biological processes and are responsible for the degradation of most (oligo)saccharides, glycolipids and glycoproteins. Malfunctioning of glycosidases... Show moreGlycosidases are essential in fundamental biological processes and are responsible for the degradation of most (oligo)saccharides, glycolipids and glycoproteins. Malfunctioning of glycosidases causes various complex pathologies in man, for example, lysosomal storage disorders such as Fabry disease and Krabbe disease. Activity-Based Protein Profiling (ABPP) is a powerful technique to selectively analyze functional proteins in their physiological surroundings. Potent and selective activity-based glycosidase probes (ABPs) could help to understand the pathological processes connected with these enzymes. The first part of this Thesis describes the design, synthesis and application of a set of ABPs for retaining α-galactosidases, β-galactosidases, α-mannosidases and β-mannosidases.Several reversible, competitive glycosidase inhibitors have been developed in the past and are employed for therapeutic applications. The second part of this Thesis focuses on the design of functionalized bicycle [4.1.0] heptanes, carba-cyclophellitols, as new potential competitive inhibitors of glycosidases (α-galactosidases, β-galactosidases, α-glucosidases and β-glucosidases) and glycosyltransferases (both galactosyltransferases and glucosyltransferases). Herein a specific substituted carba-cyclophellitol turned out to be highly potent towards Thermotoga maritima TmGH1 β-glucosidase and therefore conformational strain induced through a cyclopropyl unit may be added to the armory of tight-binding inhibitor designs. Show less

Rixel, V.H.S. van 2017

Toward selective anticancer metallodrugs

Doctoral Thesis

open access

The field of transition-metal based chemotherapeutics are dominated by derivatives of cisplatin, but a major downside of these platinum based chemotherapeutics is their lack of selectivity... Show moreThe field of transition-metal based chemotherapeutics are dominated by derivatives of cisplatin, but a major downside of these platinum based chemotherapeutics is their lack of selectivity that leads to undesirable side effects. In this work we present alternative strategies such as light-activation with different transition-metals such as ruthenium and palladium that have the potential to be more selective than cisplatin type of drugs. Show less

Luo, S. 2017

Transition metal compounds with S/N-functionalized NHC ligands: structures, redox properties and electrocatalytic activity

Doctoral Thesis

open access

The research described in this thesis focused on the preparation of S/N functionalized carbene ligands and their transition metal complexes, and the exploration of their application as... Show moreThe research described in this thesis focused on the preparation of S/N functionalized carbene ligands and their transition metal complexes, and the exploration of their application as electrocatalysts for proton reduction. Show less

Gezer, G. 2017

Biomimetic models of [NiFe] hydrogenase for electrocatalytic hydrogen evolution

Doctoral Thesis

open access

The growing demand of energy indicates that global energy resources in the form of fossil fuels will not be sufficient in the future. In order to solve potential future energy problems development... Show moreThe growing demand of energy indicates that global energy resources in the form of fossil fuels will not be sufficient in the future. In order to solve potential future energy problems development of a sustainable hydrogen economy is highly desirable. Researchers are looking for new and cleaner ways for the production of dihydrogen gas. The structure and function of hydrogenases have raised the attention of synthetic chemists in the past decades, since new catalysts for proton reduction may be developed by using biomimetic, functional models of hydrogenases. Three types of hydrogenases are known, being the [FeFe], [Fe] and [NiFe] hydrogenases.A significant amount of data has been gathered over the years concerning the enzyme redox states and the reaction mechanism for the reversible heterolytic splitting of dihydrogen at the [NiFe] hydrogenase active site. The [NiFeSe] hydrogenases form a subclass of the [NiFe] hydrogenases, in which one of the cysteines (Cys) in the active site of the enzyme is replaced by selenocysteine (Sec). This thesis deals with the synthesis and characterization of new structural and functional models of the nickel-containing enzymes [NiFe] and [NiFeSe] hydrogenases for electrocatalytic hydrogen evolution. Show less

Oussoren, S.V. 2017

Chemical biology of glucosylceramide metabolism fundamental studies and applications for Gaucher disease

Doctoral Thesis

open access

This thesis describes biochemical investigations of glucocerebrosidase (GBA), the lysosomal β- glucosidase that is deficient in Gaucher disease (GD). Central in the performed research was the... Show moreThis thesis describes biochemical investigations of glucocerebrosidase (GBA), the lysosomal β- glucosidase that is deficient in Gaucher disease (GD). Central in the performed research was the examination of factors influencing the intralysosomal stability and half-life of GBA. The investigations made use of new chemical biology tools such as activity based probes (ABPs) and photo-activatable and clickable (PAC) lipids.The Discussion reviews the present insights into GBA in health and disease. In this connection, the molecular basis and clinical manifestation of Gaucher disease and Action Myoclonus Renal Failure syndrome are discussed, including the metabolic adaptations to GBA deficiency. Particular attention is paid to the lysosomal structural stability of GBA and associated resistance against proteolytic degradation by cysteine cathepsins. Literature findings and novel own results on this topic are discussed. New technology to study GBA by labeling with GlcCer and cyclophellitol derived probes is introduced and the application is described. Unresolved research questions on GBA and related disease conditions are identified. As future research objective the translation of fundamental knowledge on GBA to effective therapy of neuronopathic Gaucher disease and other disease conditions caused by enzyme reduction are discussed. Show less

Xin, B. 2017

Discovery and development of inhibitors selective for human constitutive proteasome and immunoproteasome active sites

Doctoral Thesis

some documents under embargo

This thesis describes the design and development of subunit‐selective inhibitors of particular catalytically active subunits of human constitutive proteasomes and immunoproteasomes. Most... Show more This thesis describes the design and development of subunit‐selective inhibitors of particular catalytically active subunits of human constitutive proteasomes and immunoproteasomes. Most existing proteasome inhibitors are oligopeptides composed of 2‐4 amino acid residues, N‐terminally capped and with the C‐terminus adapted to give an electrophilic trap. Such compounds are also at the basis of the research described in this Thesis. Attention was directed to substitute specific amino acid residues by either synthetic, non‐canonical amino acid derivatives (with a review on the synthesis of such items given in Chapter 2) or dipeptide isosteres. Alternatively, modifications of the electrophilic trap, specifically, the epoxyketone moiety, were investigated. In this way, and by the synthesis of focused libraries, in which in each case a number of structural analogues, rather than a single one, inhibitors selective for β5c, β2c and β2i were discovered, and a number of two‐step activity‐based probes for probing these activities in vitro and in situ were identified. Show less

Rossius, S.G.H. 2017

'Q-wires': Synthesis, electrochemical properties and their application in electro-enzymology

Doctoral Thesis

open access

An objective of this research was to achieve direct, well-defined and non-rate-limiting electron transfer between respiratory enzymes and the electrode surface by means of 'Q-wires'. Ensuring... Show moreAn objective of this research was to achieve direct, well-defined and non-rate-limiting electron transfer between respiratory enzymes and the electrode surface by means of 'Q-wires'. Ensuring direct and fast electron transfer, these molecular wires may ultimately be part of a series of electrode surface modifications leading to the complete, stable and well-defined immobilization of an enzyme of interest. Realization of such a stable protein film may aid in the elucidation of the enzyme’s mechanism and may perhaps lead to (commercially viable) applications, such as biosensors or biofuel cells. Show less

Sweere, A.J.M. 2017

Pair configurations to molecular activity coefficients: PAC-MAC

Doctoral Thesis

open access

This thesis provides an overview of the development of the Pair Configuration to Molecular Activity Coefficient (PAC-MAC) model. PAC-MAC is a computational method to predict thermodynamic... Show moreThis thesis provides an overview of the development of the Pair Configuration to Molecular Activity Coefficient (PAC-MAC) model. PAC-MAC is a computational method to predict thermodynamic miscibility properties of various molecular solutions. Examples of calculated thermodynamic miscibility properties are vapor-liquid equilibrium (VLE) diagrams, mixing free energies and Flory-Huggins χ-interaction parameters. Within PAC-MAC, a unique approach is used by combining the quasi-chemical approximation of Guggenheim with the use of classical force fields. The quasi-chemical approximation is used in foregoing models for miscibility prediction (UNIFAC, COSMO-RS) whereas classical force fields are used in methods preserving the molecular 3D structure (molecular dynamics and Monte Carlo simulations). The combination of the quasi-chemical approximation with classical force fields results in a quick and accurate method containing, besides the force field parameters, only two empirically optimized parameters. Show less

Mirzaian, M. 2017

Analytical chemistry and biochemistry of glycosphingolipids : new developments and insights

Doctoral Thesis

open access

Advanced mass spectrometry of glycosphingolipids takes the central stage in this thesis. Investigations focus on characterization of glycosphingolipid metabolism in health and disease with... Show moreAdvanced mass spectrometry of glycosphingolipids takes the central stage in this thesis. Investigations focus on characterization of glycosphingolipid metabolism in health and disease with emphasis to the detection and accurate quantitation of known and so far unknown glycosphingolipids and closely regulated metabolites. Inherited defects in lysosomal degradation of glycosphingolipids, in particular the glycosphingolipidoses Gaucher disease (GD) and Fabry disease (FD), relatively common lysosomal storage disorders, are key topics of examination. The thesis provides an introductory background on the field of research and contains three different sections describing conducted experimental work. Section one consists of studies reporting on the discovery of excessive occurrence of glycosphingoid bases in lysosomal storage diseases, the development of methods for their accurate quantitation in biological samples with UPLC-ESI-MS/MS and the use of these methods in diagnosis and disease monitoring. The great value of identical 13C-encoded (glyco)sphingolipids and their bases as internal standards in mass spectrometric quantitation of these lipids in biological materials is described. Section two introduces clinical aspects and challenges of GD and FD and provides examples of the practical value of lipid analyses in the GD and FD clinic. Section three concerns the pathophysiology of lysosomal disorders in glycosphingolipid metabolism and related fundamental investigations. Show less

Kistemaker, H.A.V. 2017

Synthesis of well-defined ADP-Ribosylated biomolecules

Doctoral Thesis

open access

The post-translational modification of proteins known as adenosine diphosphate ribosylation (ADPr) is involved in a wide variety of important biological processes and is also associated with... Show moreThe post-translational modification of proteins known as adenosine diphosphate ribosylation (ADPr) is involved in a wide variety of important biological processes and is also associated with carcinogenesis and the process of aging. Therefore, a better understanding of the biology of ADP-ribosylation is crucial for the development of novel therapeutics. To facilitate this research, the availability of well-defined fragments of mono- and poly-ADP-ribose is essential. This Thesis describes the development of new synthetic methodologies to achieve this and the successful synthesis of well-defined ADP-ribosylated biomolecules. Show less

Deng, H. 2017

Chemical tools to modulate endocannabinoid biosynthesis

Doctoral Thesis

open access

The thesis describes the design, synthesis and application of chemical tools to study the physiological roles of DAGLa/b and MAGL in vitro and in vivo. Chapter2 reports on the design, synthesis... Show moreThe thesis describes the design, synthesis and application of chemical tools to study the physiological roles of DAGLa/b and MAGL in vitro and in vivo. Chapter2 reports on the design, synthesis and in vitro characterization of DH376 as a new dual DAGL inhibitors. In Chapter 3 the discovery of DH379 as a tailor-made activity-based probe for DAGLa/b and the effects of acute pharmacological blockade of DAGLa/b by DH376 in healthy and lipopolysaccharide-treated mice on brain lipid networks and neuroinflammation is described. Chapter 4 reports the efficacy of DH376 in refeeding behavior of fasted mice. In Chapter 5 the development of the first DAGL PET ligand [18F]DH439 is disclosed. The structure-activity relationship of disubstituted piperidinyl ureas as DAGL inhibitors is reported in Chapter 6. The design, synthesis and application of a highly selective tailor-made activity-based imaging probe for MAGL is discussed in Chapter 7. Show less

Baggelaar, M.P. 2017

Activity-based protein profiling of diacylglycerol lipases

Doctoral Thesis

open access

Diacylglycerol lipase (DAGL)-α and -β are enzymes responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol. Selective and reversible inhibitors are required to study the... Show moreDiacylglycerol lipase (DAGL)-α and -β are enzymes responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol. Selective and reversible inhibitors are required to study the function of DAGLs in neuronal cells in an acute and temporal fashion. The work described in this thesis has led to the identification of an activity-based probe (ABP) for DAGL-α. This ABP was instrumental for the identification of a new class of highly selective DAGL inhibitors.

These novel inhibitors can be used to investigate the role of the diacylglycerol lipases in metabolic syndrome and neurodegenerative diseases such a Parkinson’s disease, Alzheimer’s disease and Multiple Sclerosis.

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